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Three Part Question

In children presenting with history of non-immediate benign skin rash to penicillin therapy], [can direct provocation test] with the antibiotic [safely de-label the allergy] in acute settings?

Clinical Scenario

8-year-old boy, previously healthy presents to your emergency department with cellulitis of the right forearm. He is otherwise systemically well. You decide to prescribe flucloxacillin. His mother reports an allergy to penicillin. Allergy history reveals a maculopapular rash on day 3 of amoxicillin therapy for otitis media at 2 years of age. He has never had any penicillin antibiotic since then. A colleague suggests clindamycin. You wonder if he could tolerate flucloxacillin given the nature of the reported reaction whilst concerned about the adverse event profile of clindamycin.

Search Strategy

PubMed: 1984 to November, week 4 2020. EMBASE 1980 – 2020, week 47. Limit to age birth – 18 years AND English Language
(‘penicillin allergy’/exp) AND (‘hypersensitivity’/exp) AND (‘provocation’/exp)
(‘penicillin allergy’/exp) AND (‘provocation test’/exp OR ‘provocation test’)
(‘beta lactam allergy’/exp OR ‘beta lactam allergy’) AND challenge
(‘penicillin allergy’/exp OR ‘penicillin allergy’) AND ‘de label’ (‘penicillin allergy’/exp OR ‘penicillin allergy’) AND ‘de labelling’ ((‘penicillin’/exp OR penicillin) AND (‘allergy/exp’) AND labels AND oral AND challenge)
The Cochrane Library date of searching 27 November 2020: MeSH descriptor: [penicillin, allergy] explode all trees AND MeSH descriptor: [Child] explode all trees OR MeSH descriptor: [provocation] explode all trees
The BestBETs database was checked but no relevant BETs were found.

Search Outcome

Forty-one papers were identified after duplications, abstracts only and non-English language citations were removed. Review of the Cochrane database of systematic reviews did not reveal any additional papers. Papers of mixed adult-children population, and methodology involving prior or concurrent skin testing were excluded. Six papers answered the clinical question and summarised.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Moral et al 2011 Spain	67 patients with beta lactam hypersensitivity underwent direct oral provocation testing with index antibiotic	Prospective observational	Positive oral provocation test	Only 1 had a non-immediate (mild) reaction	Small sample size. Conflicting methodology: local protocol for low-risk symptoms used but some “high-risk” patients included
Mill et al 2016 Canada	818 children with reported immediate and non-immediate reactions to amoxicillin had graded provocative challenge (PC) with oral amoxicillin: 10% of dose followed by 90% of the dose 20 minutes later	Prospective Observational	Reactions to the graded PC	770 (94.1%) tolerated the challenge; 17 and 31 had (mild) immediate and non-immediate reactions, respectively.	Patients with a history compatible with anaphylaxis were not excluded posing safety issues. Parental reports of reactions are prone to recall and information bias.
			Negative predictive value of the PC for non-immediate reactions	Negative predictive value of 89.1%.
Vezir et al 2016 Turkey	119 children with non-immediate mild cutaneous reactions to beta lactams underwent 5-day oral provocation test (with index antibiotics)	Prospective	Tolerance to direct oral provocation test	4 patients had non-immediate (urticarial) reaction to amoxicillin-clavulanic acid. They tolerated provocation with cefuroxime.
Labrosse R et al 2018 Canada	130 children underwent a graded drug provocation test. Described as single dose graded (3 steps) challenge.	Prospective; single centred	Non-immediate reactions on 5-day challenge	122/127 were negative after 5-day challenge (note immediate reaction in 3 children).	Doubtful certainty in compliance of 5-day challenge. Relevance of prolonged challenge is debatable.
Allen et al 2020 Ireland	102 children with reported non-severe symptoms underwent DPT with single dose of penicillin and subsequently 5-day course.	Prospective Observational	Immediate reaction at DPT	No reaction recorded
			Reaction during the 5-day home course	3 children reported morbilliform rash and mild gastrointestinal symptoms
Wang et al 2020 United States	54 patients considered low risk for immediate or non-immediate penicillin hypersensitivity underwent DPT (single dose amoxicillin).	Retrospective observational	Adverse reactions (immediate and delayed) to DPT	No reactions reported	Small sample size and retrospective nature. What constituted low risk for immediate hypersensitivity was not clearly described.

Comment(s)

Many children present to the emergency departments with reported penicillin allergic reactions. Direct provocation test (DPT) is the gold standard for evaluating penicillin allergy. There is growing data to support key historical features to accurately stratify patients into low and risk groups which are crucial in application of DPT. Non-immediate mild cutaneous reactions to penicillin antibiotics are classed as low risk symptoms. The study by Mill et al provided the largest sample size in the literature that demonstrated the safety and accuracy of direct oral amoxicillin challenge in children with reported delayed benign skin rashes. British Society for Allergy and Clinical Immunology (BSACI) recommends that for children with reported non-immediate benign rash, first dose of penicillin is administered in hospital, followed by a period of monitoring of at least 2 hours. Graded challenges may not yield extra advantage over single dose challenges in the context of required resources. Although the former may provide extra information for delayed rashes, published series do not suggest a significant benefit. Of note studies where prior or concurrent skin tests in children undergoing DPT were excluded, but they strongly highlighted efficacy and safety of DPT. Removal of penicillin allergy labels reduces undesirable health care risks, antibiotic resistance, and increased costs.

Clinical Bottom Line

There is good evidence that oral DPT with penicillin is safe in non-immediate mild cutaneous reactions. This is practical in emergency and urgent care settings. However, whilst adopting this practice to foster antimicrobial stewardship, it is important to consider the 4-hour target performance indicator.

References

1. Moral L, Garde J, Toral T, et al. Short protocol for the study of paediatric patients with suspected beta lactam antibiotic hypersensitivity and low risk criteria. Allergol Immunopathol (Madr). 2011; 39(6):337-41
2. Mill C, Primeau MN, Medoff E, et al. Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children. JAMA Pediatrics. 2016 ;170(6):e160033
3. Vezir E, Dibek Misirlioglu E, Civelek E, et al. Direct oral provocation tests in non-immediate mild cutaneous reactions related to beta-lactam antibiotics. Pediatr Allergy Immunol. 2016 ;27(1):50-4
4. Labrosse R, Paradis L, Lacombe-Barrios J, et al. Efficacy and Safety of 5-Day Challenge for the Evaluation of Non severe Amoxicillin Allergy in Children. J Allergy Clin Immunol Pract. 2018 ;6(5):1673-1680
5. Allen H, Vazquez-Ortiz Marta, Murphy AW, et al. De-labeling penicillin-allergic children in outpatients using telemedicine: Potential to replicate in primary care. J Allergy Clin Immunol Pract. 2020; 8(5):1750-2
6. Wang LA, Patel K, Kuruvilla ME, et al. Direct amoxicillin challenge without preliminary skin testing for pediatric patients with penicillin allergy labels. Annals of Allergy, Asthma, and Immunology. 2020; 125(2):226-8